The following description of the background of the invention is provided to aid in understanding the invention, but is not admitted to be, or to describe, prior art to the invention. All cited publications are incorporated by reference in their entirety.
The foundation of hepatic fibrosis is that excess collagen (especially collagen I) is synthesized (Clin. Sci. 1997, 92, 103) by liver which deposits on extracellular matrix (EXM). The biosynthesis of collagen includes series of post-translational modification of procollagen. Five enzymes, 3 collagen hydroxylases and 2 collagen glycosyltransferases, are involved in this process. Among these hydroxylases, prolyl-4-hydroxylase (P4H) is a tetramer of 2 α subunits (P4Hα1, P4Hα2) and 2 β subunits. β Subunit is disulfide isomerase, and the main parts having catalytic effect locate in β Subunit, and the major role of α subunit is deciding the activity of the enzyme. Prolyl-4-hydroxylase is the rate limiting enzyme in the synthesis of 21 different collagen (Critical Reviews in Biochemistry and Molecular Biology 2010, 45, 106). P4H locates in the endoplasmic reticulum, and catalyzes the formation of 4-hydroxyproline, from the proline residue on X-Pro-Gly sequence, in the presence of Fe2+, O2, 2-oxoglutarate and ascorbate.
P4H hydroxylate proline to 4-hydorxyproline (4-HYP) in certain positions of the procollagen, thus enhances the stability of collagen by forming triple helixes under physiological circumstances. Conversely, with less 4-HYP content, the collagen is unable to form stable triple helixes structure and degrades (Matrix Biol. 2003, 22, 15). Therefore, inhibition of P4H activity is widely accepted as a valid method for controlling excess collagen synthesis (fibrosis). (Hepatol. 1998, 28, 404). Several small molecule P4H inhibitors were verified to be effective in preventing collagen synthesis in vitro and in vivo (J. Hepatol. 1997, 27, 185; Hepatol. 1996, 23, 755; Hepatol. 1998, 28, 404; Biochem. J. 1994, 300, 525; J. Hepatol. 1991, 13, S35). For example, P4H inhibitor HOE077 inhibits expression of procollagen mRNA and reduces hepatic stellate cells proliferation (Hepatol. Res. 2002, 23, 1; J. Hepatol. 1997, 27, 185), also inhibits activation of hepatic stellate cells (Hepatol. 1996, 23, 755). The inhibitory effect of HOE077 on procollagen gene and protein was dose-dependent, but no effect on the synthesis of total protein of cell was observed. The inhibitory effect of HOE077 is possibly due to the inhibition of the expression of TIMP gene to expedite collagen degradation process (J. Gastroenterol. 1999, 34, 376). Several P4H inhibitors showed anti-fibrotic effects in various animal liver fibrosis models (CO4, TAA etc.). (Hepatol. 1998, 28, 404; Hepatol. 1996, 23, 755; J. Hepatol. 1997, 27, 185). Another P4H inhibitor FG-041 (1,4-dihydrophenanthrol-4-one-3-carboxylic acid) was reported to prevent myocardial infarction in animal experiment (Circulation 2001, 104, 2216). P4H inhibitors were also reported to prevent bladder block (Urology 2012, 80, 1390).
P4H exists everywhere in body. Thus, P4H inhibitors is targeted-delivered to diseased organ while the other normal organ don't be influenced, is the key to successful development of safe and effective P4H inhibitors. In 1990s, HOECHST (which is france sanofi now) firstly developed HOE077 to treat liver cirrhosis (Hepatol. 1996, 23, 755; J. Hepatol. 1997, 27, 185). Preclinical experiments showed promising results though severe side effects (cataract) were observed in clinical trials. It is reported that inhibition of collagen synthesis could seriously influence the function of organ, such as eyes and kidneys (J. Biol. Chem. 2010, 285, 42023). Collagen synthesis widely exists in cellular matrix, therefore, the suppression of collagen synthesis of organ cell matrix results in the effusion of macromolecules, which cause the change of the organ function. Thus, the key to developing the P4H inhibitors used to treat organ fibrosis (such as liver fibrosis) is how to deliver the P4H inhibitors to specified organ. Prodrugs have been widely used in targeted therapeutic areas (J. Pharmacol. Exp. Ther. 2005, 312, 554). 1,3-Propane diols could form cyclic phosphonate esters with phosphonic acids, which were reported liver targeting (J. Med. Chem. 2008, 51, 666). The liver prodrug-delivery which the present invention adopts is to modify the active component of the drug to inactive prodrug. The prodrug may only be metabolized under the catalysis of liver-specific enzymes, for example, cytochrome P450, to release the active component in liver, therefor the active component produce effect in liver.
Content of the Present Invention
The purpose of the present invention is to provide a novel phenantholine phosphonic acid compound and the pharmaceutical salt thereof. The another purpose of the present invention is to provide a preparation of the compound and the pharmaceutical salt thereof. The another purpose of the present invention is to provide an application of the compound and the pharmaceutical salt thereof as collagen prolyl-4-hydroxylase inhibitors in the preparation of drugs for preventing or treating collagen prolyl-4-hydroxylase related disease.
In one aspect, the present invention provides compounds of Formula I or Formula II, and pharmaceutically acceptable salts thereof:

Wherein, in Formula I:
X is —Cl or —OR3; R3 is —H, —C(O)—(C1-C6 alkyl), —PO(OH)2 or —CH2OPO(OH)2;
Each of R1 and R2 can be independently selected from H, C1-C6 alkyl, —CH2OCO—(C1-C6 alkyl) and CH2OCOO—(C1-C6 alkyl); or R1 and R2 join to form a group having the formula:

Wherein Y is aryl or heteroaryl;
In one aspect, X could be selected from —Cl, and —OR3, R3 is —H, —C(O)—(C1-C6 alkyl), —PO(OH)2 or —CH2OPO(OH)2;
In another aspect, each of R1 and R2 could be independently selected from H, C1-C6 alkyl, —CH2OCO—(C1-C6 alkyl) and —CH2OCOO—(C1-C6 alkyl); or R1 and R2 join to form a group having the formula:

Wherein Y is aryl, heteroaryl;
Wherein, in Formula II:
Z is —H or —CH2OPO(OH)2; each of R1 and R2 is independently selected from H, C1-C6 alkyl, —CH2OCO—(C1-C6 alkyl) and —CH2OCOO—(C1-C6 alkyl); or R1 and R2 join to form a group having the formula:

Wherein Y is aryl or heteroaryl.
In one aspect, Z could be selected from —H, and CH2OPO(OH)2;
In another aspect, each of R1 and R2 can be independently selected from H, C1-C6 alkyl, —CH2OCO—(C1-C6 alkyl) and —CH2OCOO—(C1-C6 alkyl); or R1 and R2 join to form a group having the formula:

Wherein Y is aryl, heteroaryl.
In a preferred embodiment, the compound have the following formula:

In another preferred embodiment, the compound have the following formula:

In another preferred embodiment, the compound have the following formula:

In the second aspect, the present invention provides the method of preparing the phenantholine phosphonic acid compound and the pharmaceutical salt thereof.
In the third aspect, the present invention provides an application of the phenantholine phosphonic acid compound and the pharmaceutical salt thereof as collagen prolyl-4-hydroxylase inhibitors in the preparation of drugs for preventing or treating collagen prolyl-4-hydroxylase related disease.
The present invention provides an application of the compounds of Formula I or Formula II or the pharmaceutical salt thereof in the preparation of drugs for preventing or treating collagen prolyl-4-hydroxylase related disease.
The present invention provides an application of the compounds of Formula I or Formula II, or the in vivo metabolite thereof, or the pharmaceutical salt thereof used as collagen prolyl-4-hydroxylase inhibitors.
The present invention could protect liver function by administering to a patient with chronic liver injuries a therapeutically effective amount of the compound of Formula I and Formula II, or pharmaceutically acceptable salts thereof.
The present invention could prevent and treat liver fibrosis by administering to a patient with chronic liver injuries a therapeutically effective amount of the compound of Formula I and Formula II, or pharmaceutically acceptable salts thereof.
The present invention could prevent liver fibrosis by administering to a patient at risk for developing diabetes a therapeutically effective amount of the compound of Formula I and Formula II, or pharmaceutically acceptable salts thereof.